This invention relates to a chimeric antibody and a method for its use in targeting at least one diagnostic or therapeutic agent to an inflammatory or infectious lesion. The chimeric antibody includes an antigen-binding variable region that specifically binds to an epitope on human granulocytes and a constant region having an Fc portion that has a high affinity for receptors on human mononuclear lymphoid cells. Such chimeric antibodies are conjugated to a suitable diagnostic label or therapeutic agent for targeting to sites of infection or inflammation.
The value of labeling granulocytes with radionuclides to detect occult infection and inflammation has been appreciated for some time. Granulocytes, mononuclear blood cells and platelets have been labeled by incubation with various In-111 salts or simple In-111 organic ligands. This method requires isolation of the cells from blood prior to labeling and is laborious and time-consuming.
More recently, it has been demonstrated that radiolabeled murine anti-granulocyte antibodies are also effective for imaging occult infections, as an alternative to pre-labeled granulocytes. The labeled antibodies can be injected directly into the vascular system, eliminating the need for the laborious task of cell isolation. In U.S. Pat. No. 4,634,586 (Goodwin et al.), incorporated herein by reference in its entirety, leukocytes are radioimmunoimaged by injecting patients with an immunoreactive nonleukocidal conjugate of an anti-leukocyte monospecific antibody and a gamma emitting radioactive metal chelate, waiting for the conjugate to localize on the leukocytes, injecting a patient with an antibody to the conjugate to clear the blood of background nonlocalized conjugate, and visualizing the leukocytes by scintillation scanning.
It is also known that radiolabeled human polyclonal IgG can be used to image occult infection and inflammation. These antibodies appear to localize at such sites due to interaction of the Fc moiety of a subpopulation of the radiolabeled IgG with mononuclear cells present at the disease site.
The problem that limits the optimal practice of the use of antibodies to granulocytes to detect occult infection or inflammation is the fact that as the disease process is contained, the granulocyte population in the lesion is reduced and replaced by mononuclear lymphoid cells (MLC's), i.e., monocytes, T-cells, B-cells and/or nonspecific killer cells (NK-cells), that appear to bear high affinity Fc-receptors. The ratio of granulocytes to MLC's can also vary markedly as a function of the type of infectious agent which initiates the lesion. Thus, anti-granulocyte antibodies will not be as effective for imaging later stages of infection or inflammation as earlier, more acute stages or for imaging lesions having a low granulocyte level for other reasons.
Moreover, it has been found that nonspecific IgG also localizes in certain types of cancers (see, e.g., Rubin et al., N. Eng. J. Med., 321:935-940, 1989) so that the granulocyte specificity of the conjugate of the present invention permits better descrimination between cancerous and non-cancerous legions.
Leukocyte imaging has been severely limited in the prior art due to poor target to background ratio. It has been shown that the localization ratio can be increased, for example, by using second antibody clearance. However, the target to background ratio remains a problem when using a mixture of anti-leukocyte antibodies because each targeting antibody normally binds to a specific leukocyte cell type, either a granulocyte, a monocyte, a B-lymphocyte or a T-lymphocyte. Therefore, there will be many antibodies that are highly reactive and specific for a particular leukocyte cell in the background that have not bound to the target site, because that particular leukocyte cell type is not present at significant levels at the site of infection or inflammation.
One solution to the foregoing problems is disclosed in applicants' copending and commonly assigned patent application, Hansen et al., U.S. Ser. No. 07/226,180, filed July 29, 1988 (issued as U.S. Pat. No. 4,925,648 on May 15, 1990), which is incorporated by reference herein in its entirety. That application discloses a polyspecific antibody composite conjugate having affinity for more than one type of leukocyte. A diagnostic or therapeutic agent targeted with such a conjugate will be localized to the lesion with lesser dependence upon the particular type of leukocyte which predominates at the site of the lesion.
There is a need for alternative or extended solutions to these problems.